[Cystic fibrosis: A report of 33 pediatric Tunisian cases]. / La mucoviscidose chez L'Enfant Tunisien: a porpos de 33 observations.

BACKGROUND: The frequency of cystic fibrosis is unknown in Tunisia, regarding the limited number of reported surveys and patients. AIM: to determine the clinical characteristics, outcome and genetic data of cystic fibrosis in Tunisian pediatric patients. METHODS: Cases of cystic fibrosis managed at pediatric departments of Tunis, during 15 years (1997-2012), were reviewed. RESULTS: 33 children (23 males and 10 females) were enrolled. The Onset was within the first year of life in 26 patients. Revealing symptoms were the following: recurrent bronchopneumonia (28 cases), chronic diarrhea (17 cases), hepatomegaly (6 cases), malnutrition (15 cases), pseudo Bartter syndrome (3 cases), edemaanemia- hypoprotidemia (4 cases) and meconium ileus (4 cases). The diagnosis was confirmed by sweat test and genotypic data, the F508 del was the most frequent mutation (17 cases). Several complications had occurred during follow-up: chronic pseudomonas aeruginosa infection (15 cases), chronic respiratory failure (14 cases), recurrent hemoptysis (2 cases), pleural effusion (3 cases) and cirrhosis (2 cases). Ten patients died at a mean age of 7 years. One patient had pulmonary transplantation. Prenatal diagnosis was performed in 9 families. CONCLUSION: In Tunisia, cystic fibrosis is not exceptional, but its diagnosis is delayed. Our survey is characterized by more severe earliest forms, difficult and insufficient therapeutic management. A Better medical awareness and a national action plan are needed.

Molecular and biochemical characterization of a novel intronic single point mutation in a Tunisian family with glycogen storage disease type III.

Genetic deficiency of the glycogen debranching enzyme causes glycogen storage disease type III, an autosomal recessive inherited disorder. The gene encoding this enzyme is designated as AGL gene. The disease is characterized by fasting hypoglycemia, hepatomegaly, growth retardation, progressive myopathy and cardiomyopathy. In the present study, we present clinical features and molecular characterization of two consanguineous Tunisian siblings suffering from Glycogen storage disease type III. The full coding exons of the AGL gene and their corresponding exon-intron boundaries were amplified for the patients and their parents. Gene sequencing identified a novel single point mutation at the conserved polypyrimidine tract of intron 21 in a homozygous state (IVS21-8A>G). This variant cosegregated with the disease and was absent in 102 control chromosomes. In silico analysis using online resources showed a decreased score of the acceptor splice site of intron 21. RT-PCR analysis of the AGL splicing pattern revealed a 7 bp sequence insertion between exon 21 and exon 22 due to the creation of a new 3' splice site. The predicted mutant enzyme was truncated by the loss of 637 carboxyl-terminal amino acids as a result of premature termination. This novel mutation is the first mutation identified in the region of Bizerte and the tenth AGL mutation identified in Tunisia. Screening for this mutation can improve the genetic counseling and prenatal diagnosis of GSD III.

Velaglucerase alfa enzyme replacement therapy compared with imiglucerase in patients with Gaucher disease.

Enzyme replacement therapy for Gaucher disease (GD) has been available since 1991. This study compared the efficacy and safety of velaglucerase alfa with imiglucerase, the previous standard of care. A 9-month, global, randomized, double-blind, non-inferiority study compared velaglucerase alfa with imiglucerase (60 U/kg every other week) in treatment-naïve patients aged 3-73 years with anemia and either thrombocytopenia or organomegaly. The primary endpoint was the difference between groups in mean change from baseline to 9 months in hemoglobin concentration. 35 patients were randomized: 34 received study drug (intent-to-treat: 17 per arm), 20 were splenectomized. Baseline characteristics were similar in the two groups. The per-protocol population included 15 patients per arm. The mean treatment difference for hemoglobin concentration from baseline to 9 months (velaglucerase alfa minus imiglucerase) was 0.14 and 0.16 g/dL in the intent-to-treat and per-protocol populations, respectively. The lower bound of the 97.5% one-sided confidence interval in both populations lay within the pre-defined non-inferiority margin of -1.0 g/dL, confirming that velaglucerase alfa is non-inferior to imiglucerase. There were no statistically significant differences in the secondary endpoints. Most adverse events were mild to moderate. No patient receiving velaglucerase alfa developed antibodies to either drug, whereas four patients (23.5%) receiving imiglucerase developed IgG antibodies to imiglucerase, which were cross-reactive with velaglucerase alfa in one patient. This study demonstrates the efficacy and safety of velaglucerase alfa compared with imiglucerase in adult and pediatric patients with GD clinically characterized as Type 1. Differences in immunogenicity were also observed.

High frequency of W1327X mutation in glycogen storage disease type III patients from central Tunisia.

Glycogen storage disease type III (GSD III) is an autosomal recessive disorder caused by the deficiency of glycogen debranching enzyme (AGL). It is characterized by hepatomegaly, progressive myopathy, cardiomyopathy and fasting hypoglycemia. Several mutations in AGL gene have been described in different populations. The W1327X mutation was reported in one Tunisian patient resident in Italy. We looked in this report to determine the frequency of W1327X mutation among Tunisian patients. The W1327X mutation was screening in 26 GSD III patients originated from various geographic locations in Tunisia. The sequence analysis revealed that among nine patients carried the W1327X mutation. Eight of them were from six unrelated families and they were originated from Mahdia (centre of Tunisia) suggesting the existence of a founder effect in this region. Taking into account historical migratory waves, screening for this mutation should be performed in priority for molecular diagnosis confirmation of GSD III in North African populations.

Hurler disease (mucopolysaccharidosis type IH): clinical features and consanguinity in Tunisian population.

UNLABELLED: Mucopolysaccharidosis type I (MPS I) was a group of rare autosomal recessive disorder caused by the deficiency of the lysosomal enzyme, alpha -L -iduronidase, and the resulting accumulation of undergraded dematan sulfate and heparan sulfate. MPS I patients have a wide range of clinical presentations, that makes it difficult to predict patient phenotype which is needed for genetic counseling and also impedes the selection and evaluation of patients undergoing therapy bone marrow transplantation. AIM OF THE STUDY: consanguinity rates have been determined among 14 families with mucopolysaccharidosis type I, seen in the pediatric departments of different geographic areas of Tunisia (Central and Southern areas) for the period August 2004 - August 2011 in order to investigate the relation between consanguinity and this disorder. PATIENTS AND METHODS: Clinical and molecular analyses confirmed the diagnosis for MPS type I in the studied families. RESULTS: Most of the Tunisian MPS I patients have been identified at the homozygous status: p.P533R mutation (7 homozygous and one double heterozygous p.L578Q/p.P533R patients; 41.66% of all the investigated MPSI patients), p.F177S (1 homozygous patient; 5.55%), p.L530fs (1 patient; 5.55%), p.Y581X (2 patients; 11.11%), p.F602X (3 patients; 16.66%), p.R628X (1 patient; 5.55%). Another mutation: p.L578Q has been identified at the heterozygous status in the only double heterozygous p.L578Q/p.P533R case. Part of the mutations was the result of a founder effect. These described points are the consequences of the high rate of consanguinity. CONCLUSION: The high frequency of p.P533R mutation could be explained by the high degree of inbreeding. This is due to the richness of the genetic background of the studied population.A multidisciplinary approach is essential to develop adequate preventive program adapted to the social, cultural, and economic context.

Phenylketonuria is still a major cause of mental retardation in Tunisia despite the possibility of treatment.

BACKGROUND AND OBJECTIVE: Accumulation of phenylalanine following a deficiency of phenylalanine hydroxylase activity generates a brain damage with mental retardation: phenylketonuria (PKU). In the developing countries, where PKU systematic neonatal screening program is not established yet, the management of PKU handicap is not properly carried out. The aim of this study was to estimate the frequency of the PKU diagnosed following clinical features anomalies, to provide information about the untreated PKU patients profile in Tunisia not covered by neonatal screening. Also it is stressed that treated patients have a normal development. PATIENTS AND METHODS: This is a retrospective study of 156 cases of PKU detected in Tunisia over 20 years following symptoms suggestive of inherited metabolic disease. Phenylalaninemia level was performed by fluorometric method. Among them 9 patients were treated. RESULTS: The PKU estimated frequency was 1/7631. The diagnosis mean age was 4 years. The phenylalaninemia mean was 1680 µmol/L; the classical PKU form accounted for 85.3% of cases and the dominant clinical symptoms were: mental retardation (88.2%), motor delays (87.7%), speech difficulties (83.2%) and pigmentation anomalies (61.7%). The treated patients responded to treatment and showed a normal development. CONCLUSION: The establishment of neonatal screening should be a priority to avoid cases of mentally retardation.

Mucopolysaccharidosis type I: molecular characteristics of two novel alpha-L-iduronidase mutations in Tunisian patients.

BACKGROUND: Mucopolysaccharidosis type I (MPS I) is an autosomal storage disease resulting from defective activity of the enzyme α-L-iduronidase (IDUA). This glycosidase is involved in the degradation of heparan sulfate and dermatan sulfate. MPS I has severe and milder phenotypic subtypes. AIM OF STUDY: This study was carried out on six newly collected MPS I patients recruited from many regions of Tunisia. PATIENTS AND METHODS: Mutational analysis of the IDUA gene in unrelated MPS I families was performed by sequencing the exons and intron-exon junctions of IDUA gene. RESULTS: Two novel IDUA mutations, p.L530fs (1587_1588 insGC) in exon 11 and p.F177S in exon 5 and two previously reported mutations p.P533R and p.Y581X were detected. The patient in family 1 who has the Hurler phenotype was homozygous for the previously described nonsense mutation p.Y581X.The patient in family 2 who also has the Hurler phenotype was homozygous for the novel missense mutation p.F177S. The three patients in families 3, 5 and 6 were homozygous for the p.P533R mutation. The patient in family 4 was homozygous for the novel small insertion 1587_1588 insGC. In addition, eighteen known and one unknown IDUA polymorphisms were identified. CONCLUSION: The identification of these mutations should facilitate prenatal diagnosis and counseling for MPS I in Tunisia.

[Rosai -Dorfman disease: a two cases report]. / La maladie de Rosai ­ Dorfman : a propos de deux observations.

BACKGROUND: Rosai-Dorfman disease (RDD) is a benign lymphoproliferatif disorder characterized by cervical lymphadenopathies with a consistent risk of airways' compression and esthetical prejudice. Extra nodal localizations are also described. AIM: To report two pediatric cases of RDD. CASES: the first case concerned a patient with a prolonged nodal involvement of RDD. Remission seems to be natural although it coincided with a sulfaméthoxazole- triméthoprime therapy. The second case illustrated an extranodal form of RDD localized in soft tissue and paranasal sinus with extension to nasal cavity which were corticodependant. CONCLUSION: RDD is usually a benign disorder. Particular localizations, lack of effective therapy and the high risk of recurrence are important issues in this rare affection.

[A novel mutation in PEX 26 gene in Zellweger syndrome: a case report]. / Syndrome de Zellweger par une nouvelle mutation du gène PEX 26.

BACKGROUND: Zellweger syndrome is the most severe phenotype of the peroxisome biogenesis disorders caused by mutations in PEX genes. PEX 1, 6 and 26 genes are most frequently implicated. Clinical phenotype can't predict the mutated gene. AIM: To report a novel mutation in the PEX 26 gene in infant with typical Zellweger syndrome. CASE REPORT: the infant was the second child to consanguineous parents; the 1st child was dead with neonatal hypotonia. At two month of age, we noted a severe hypotonia and growth failure, characteristic facial dysmorphic features and cryptorchidism. Sensorial investigations showed optic atrophy. Cerebral tomography revealed white matter hypodensity. Radiological examination revealed calcific stippling of the patellas. The clinical diagnosis was supported by measurement of plasma very-long-chain fatty acids, with elevated C24:0/C22:0, C26:0/C22:0 ratios and decreased docosanoic acid peak. The diagnosis was confirmed by dosage of DHAP-AT activity in fibroblasts which was very low. Ultrastructural examinations showed the presence of peroxisomal ghosts. Genetic analysis demonstrated a new mutation in PEX 26 gene.The death occurred at the age of 8 months of refractor epilepsy and apneas. CONCLUSION: The poor prognosis of ZS incites paediatricians to consider this disorder in etiological investigations of precocious hypotonia. Biochemical diagnosis, available in Tunisia, offers opportunity of prenatal diagnosis in affected families.

[Visceral leishmaniasis in children: prognostic factors]. / La leishmaniose viscérale chez l'enfant: facteurs pronostiques.

The morbidity and death rate of visceral leishmaniasis (VL) is important. The aim of our study is to find prognosis factors of VL. Two hundred and thirty two children with VL were retrospectively studied. These children were followed in Rabta and Kairouan hospitals between 1985 and 1998. We identify 7 prognosis factors, at the hospital admission, visit delayed more than 56 days, fever during more than 21 days, normal or low temperature, haemorrhagic syndrome hemoglobin rate < 5.5 g/dl, sedimentation rate < 25 mm and hypoalbuminaemia < 30 g/l. The presence of one prognosis factors or more appears to consider amphotericin B as a first-line treatment.

[Immunological study in sickle cell disease patients: importance of the complement system]. / Etude immunologique du drepanocytaire homozygote: importance du systeme complementaire.

Ten Tunisian patients, with homozygote sickle cell disease and asplenia were studied to investigate and to determine possible immunological function defects. Obtained results directed us to an abnormality of the alternate complement pathway activation which is expressed by a decreased hémolytic activity, while the classic pathway is normal. Quantification of C3, C4, C5, C6, C7 and factor B by immunochemical assay were normal, whereas factor B functional activity was depressed to a mean level of about half of normal in eight patients, IgG was increased in one subject and IgA in two others. Numeration of Band T cells revealed slight decrease in proportion of CD3 and CD4 at one patient associated with an increase in B cells, but normal or increased absolute numbers of all cells population.

[Pulmonary aspergillosis in a child with chronic granulomatous disease]. / Aspergillose pulmonaire invasive chez un enfant porteur d'une granulomatose septique chronique.

The chronic granulomatous disease is characterised by the occurence of multiple bacterial and fungal infections since the early childhood. This susceptibility to infections must be prevented by a primary prophlylaxis against the opportunistic germs like pneumocystis and aspergillus. Our case is about a twelve-year-old boy who had a prophylaxis since his fourth month of life. At 10 years he presented a pleuro-pneumonia refractory to a large spectrum antibiotherapy. The aspergillar etiology was established on clinical, radiological and serological arguments. An amphotericine B treatment allowed a good clinical and radiological outcome of this pleuro-pulmonary affection. However, a dorsal spondylodiscitis complicated the course of the disease. A secondary vertebral aspergillosis or a Pott's disease were suspected. The vertebral bipsy was'nt conclusive. The association of antituberculous and antifungal agents with adjuvant molecules (IFN, granulotic transfusions and GM-CSF) permitted a good clinical outcome and the stabilisation of the radiological lesions.

[Bronchopulmonary aspergillosis: study of 17 cases]. / L'aspergillose broncho-pulmonaire: etude de 17 cas.

Aspergillosis is a fungic infection depending on the local or general physiologic and immunologic state of the host. We report the result of retrospective five year study (1995-1999) about 17 cases in the laboratory of Parasitology-Mycology of Rabta hospital in Tunis. Six aspergillomas were observed, they occurred after a pulmonary tuberculosis, two cases of allergic broncho-pulmonary aspergillosis described in two asthmatic patients, nine cases of invasive pulmonary aspergillosis complicating two cancers, one leukaemia, six chronic granulomatous disease. Aspergillus fumigatus is the most frequent species (67%). The clinical and biological characteristic of those will be studied, and compared with those of the literature.